Consideration of quality of life in the health technology assessments of rare disease treatments

Objectives Challenges with patient-reported outcome (PRO) evidence and health state utility values (HSUVs) in rare diseases exist due to small, heterogeneous populations, lack of disease knowledge and early onset. To better incorporate quality of life (QoL) into Health Technology Assessment, a clearer understanding of these challenges is needed. Methods NICE appraisals of non-oncology treatments with an EMA orphan designation (n=24), and corresponding appraisals in the Netherlands, France, and Germany were included. Document analysis of appraisal reports investigated how PROs/ HSUVs infuenced decision-making and was representative of QoL impact of condition and treatment. Results PRO evidence was not included in 6/24 NICE appraisals. When included, it either failed to demonstrate change, capture domains important for patients, or was uncertain. In the other countries, little information was reported and evidence largely did not demonstrate change. In NICE appraisals, HSUVs were derived through the collection of EQ-5D data (7/24 cases), mapping (6/24), vignettes (5/24), and published literature or other techniques (6/24). The majority did not use data collected alongside clinical trials. Few measures demonstrated signifcant change due to lack of sensitivity or face validity, short-term data, or implausible health states. In 8/24 NICE appraisals, patient surveys or input during appraisal committee meetings supported the interpretation of uncertainty or provided evidence about QoL. Conclusions This study sheds light on the nature of PRO evidence in rare diseases and associated challenges. Results emphasise the need for improved development and use of PRO/HSUVs. Other forms of evidence and expert input are crucial to support better appraisal of uncertain or missing evidenc

Implementing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments:Nusinersen and Tisagenlecleucel

Enthusiasm for the use of outcomes-based managed entry agreements (OBMEAs) to manage uncertainties apparent at the time of appraisal/pricing and reimbursement of new medicines has waned over the past decade, as challenges in establishment, implementation and re-appraisal have been identified. With the recent advent of innovative treatments for rare diseases that have uncertainties in the clinical evidence base, but which could meet a high unmet need, there has been renewed interest in the potential of OBMEAs. The objective of this research was to review the implementation of OBMEAs for two case studies across countries in the European Union, Australia and Canada, to identify good practices that could inform development of tools to support implementation of OBMEAs. To investigate how OBMEAs are being implemented with rare disease treatments, we collected information from health technology assessment/payer experts in countries that had implemented OBMEAs for either nusinersen in spinal muscular atrophy or tisagenlecleucel in two cancer indications. Operational characteristics of the OBMEAs that were publicly available were documented. Then, the experts discussed issues in implementing these OBMEAs and specific approaches taken to overcome challenges. The OBMEAs identified were based on individual outcomes to ensure appropriate use, manage continuation of treatment and in two cases linked to payment schedules, or they were population based, coverage with evidence development. For nusinersen, population-based OBMEAs are documented in Belgium, England and the Netherlands and individual-based schemes in Bulgaria, Ireland, Italy and Lithuania. For tisagenlecleucel, there were population-based schemes in Australia, Belgium, England and France and individual-based schemes in Italy and Spain. Comparison of the OBMEA constructs showed some clear published frameworks and clarity of the uncertainties to be addressed that were similar across countries. Agreements were generally made between the marketing authorisation holder and the payer with involvement of expert physicians. Only England and the Netherlands involved patients. Italy used its long-established, national, web-based, treatment-specific data collection system linked to reimbursement and Spain has just developed such a national treatment registry system. Other countries relied on a variety of data collection systems (including clinical registries) and administrative data. Durations of agreements varied for these treatments as did processes for interim reporting. The processes to ensure data quality, completeness and sufficiency for re-analysis after coverage with evidence development were not always clear, neither were analysis plans. These case studies have shown that important information about the constructs of OBMEAs for rare disease treatments are publicly available, and for some jurisdictions, interim reports of progress. Outcomes-based managed entry agreements can play an important role not only in reimbursement, but also in treatment optimisation. However, they are complex to implement and should be the exception and not the rule. More recent OBMEAs have developed document covenants among stakeholders or electronic systems to provide assurances about data sufficiency. For coverage with evidence development, there is an opportunity for greater collaboration among jurisdictions to share processes, develop common data collection agreements, and share interim and final reports. The establishment of an international public portal to host such reports would be particularly valuable for rare disease treatments

Research priorities for mitochondrial disorders: Current landscape and patient and professional views

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease-modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively-funded research designed by academics meets core needs of people with mitochondrial disorders and their clinicians. The Priority Setting Partnerships are an established collaborative methodology that brings patients, carers and families, charity representatives and clinicians together to try to establish the most pressing and unanswered research priorities for a particular disease. We developed a web-based questionnaire, requesting all patients affected by primary mitochondrial disease, their carers, and clinicians to pose their research questions. This yielded 709 questions from 147 participants. These were grouped into overarching themes including basic biology, causation, health services, clinical management, social impacts, prognosis, prevention, symptoms, treatment, and psychological impact. Following the removal of 'answered questions' the process resulted in a list of 42 discrete, answerable questions. This was further refined by web-based ranking by the community to 24 questions. These were debated at a face-to-face workshop attended by a diverse range of patients, carers, charity representatives and clinicians to create a definitive 'Top Ten of unanswered research questions for primary mitochondrial disorders'. These Top Ten questions related to understanding biological processes, including triggers of disease onset, mechanisms underlying progression and reasons for differential symptoms between individuals with identical genetic mutations; new treatments; biomarker discovery; psychological support; and optimal management of stroke-like episodes and fatigue

Research priorities for mitochondrial disorders: current landscape and patient and professional views

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease-modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively-funded research designed by academics meets core needs of people with mitochondrial disorders and their clinicians. The Priority Setting Partnerships are an established collaborative methodology that brings patients, carers and families, charity representatives and clinicians together to try to establish the most pressing and unanswered research priorities for a particular disease. We developed a web-based questionnaire, requesting all patients affected by primary mitochondrial disease, their carers, and clinicians to pose their research questions. This yielded 709 questions from 147 participants. These were grouped into overarching themes including basic biology, causation, health services, clinical management, social impacts, prognosis, prevention, symptoms, treatment, and psychological impact. Following the removal of ‘answered questions’ the process resulted in a list of 42 discrete, answerable questions. This was further refined by web-based ranking by the community to 24 questions. These were debated at a face-to-face workshop attended by a diverse range of patients, carers, charity representatives and clinicians to create a definitive ‘Top Ten of unanswered research questions for primary mitochondrial disorders’. These Top Ten questions related to understanding biological processes, including triggers of disease onset, mechanisms underlying progression and reasons for differential symptoms between individuals with identical genetic mutations; new treatments; biomarker discovery; psychological support; and optimal management of stroke-like episodes and fatigue

Reporting the whole story : Analysis of the 'out-of-scope' questions from the James Lind Alliance Teenage and Young Adult Cancer Priority Setting Partnership Survey

OBJECTIVE: We conducted a UK-wide survey to identify the top 10 research questions for young people's cancer. We conducted secondary analysis of questions submitted, which were 'out-of-scope' of the original survey aim. We sought to disseminate these questions, to inform practice, policy and the development of potential interventions to support young people with cancer. DESIGN: James Lind Alliance Priority Setting Partnership. PARTICIPANTS: Young people aged 13-24 with a current/previous cancer diagnosis, their families/friends/partners and professionals who work with this population. METHODS: Eight hundred and fifty-five potential research questions were submitted, and 326 were classified as 'out-of-scope'. These questions, along with 49 'free-text' comments, were analysed using thematic analysis. RESULTS: The 375 out-of-scope questions and comments were submitted by: 68 young people, 81 family members/partners/friends and 42 professionals. Ten overarching themes were identified: diagnostic experience; communication; coordination of care; information needs and lack of information; service provision; long-term effects and aftercare support; family support; financial impact; end-of life care; and research methods and current research. CONCLUSIONS: The need to tailor services, information and communication is a striking thread evidenced across the 'out-of-scope' questions. Gaps in information highlight implications for practice in revisiting information needs throughout the cancer trajectory. We must advocate for specialist care for young people and promote the research priorities and these findings to funding bodies, charities, young people and health and social care policymakers, in order to generate an evidence base to inform effective interventions across the cancer trajectory and improve outcomes. PATIENT/PUBLIC CONTRIBUTIONS: Patients and carers were equal stakeholders throughout

Research priorities for young people with cancer : a UK priority setting partnership with the James Lind Alliance

OBJECTIVES: To conduct a UK-wide survey of young people who have experienced cancer, carers and professionals, to identify and prioritise research questions to inform decisions of research funders and support the case for research with this unique cancer population. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative and partner organisations were recruited. Unanswered questions were collected in an online survey. Evidence searching verified uncertainties. An interim survey was used to rank questions prior to a final prioritisation workshop. PARTICIPANTS: Young people aged 13-24 years with a current or previous cancer diagnosis, their families, friends, partners and professionals who work with this population. RESULTS: Two hundred and ninety-two respondents submitted 855 potential questions. Following a refining process and removal of 'out of scope' questions, 208 unique questions remained. Systematic evidence checking identified seven answered questions and 16 were the subject of ongoing studies. The interim survey was completed by 174 participants. The top 30 questions were prioritised at a workshop attended by 25 young people, parents and multidisciplinary professionals. The top three priorities are: (1) What psychological support package improves psychological well-being, social functioning and mental health during and after treatment? (2) What interventions, including self-care, can reduce or reverse adverse short-term and long-term effects of cancer treatment? (3) What are the best strategies to improve access to clinical trials? The remaining questions reflect the complete cancer pathway: new therapies, life after cancer, support, education/employment, relapse and end-of-life care. CONCLUSIONS: We have identified shared research priorities for young people with cancer using a rigorous, person-centred approach involving stakeholders typically not involved in setting the research agenda. The breadth of priorities suggest future research should focus on holistic and psychosocial care delivery as well as traditional drug/biology research

HTA programme response to the challenges of dealing with orphan medicinal products:Process evaluation in selected European countries

Background Challenges commonly encountered in HTA of orphan medicinal products (OMPs) were identified in Advance-HTA. Since then, new initiatives have been developed to specifically address issues related to HTA of OMPs. Objective and methods This study aimed to understand why these new HTA initiatives in England, Scotland and at European-level were established and whether they resolve the challenges of OMPs. The work of Advance-HTA was updated with a literature review and a conceptual framework of clinical, regulatory and economic challenges for OMPs was developed. The new HTA programmes were critiqued against the conceptual framework and outstanding challenges identified. Results The new programmes in England and Scotland recognise the challenges identified in demonstrating the value of ultra-OMPs (and OMPs) and that they require a different process to standard HTA approaches. Wider considerations of disease and treatment experiences from a multi-stakeholder standpoint are needed, combined with other measures to deal with uncertainty (e.g. managed entry agreements). While approaches to assessing this new view of value of OMPs, extending beyond cost/QALY frameworks, differ, their criteria are similar. These are complemented by a European initiative that fosters multi-stakeholder dialogue and consensus about value determinants throughout the life-cycle of an OMP. Conclusion New HTA programmes specific to OMPs have been developed but questions remain about whether they sufficiently capture value and manage uncertainty in clinical practice

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL)

International audienceAbstractRare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP’s is realised